Loss Of Long-term Potentiation Research Articles

Preventive exercise and physical rehabilitation promote long-term potentiation-like plasticity expression in patients with multiple sclerosis.

Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS). In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation.

Serotonin drives striatal synaptic plasticity in a sex-related manner

IntroductionPlasticity at corticostriatal synapses is a key substrate for a variety of brain functions – including motor control, learning and reward processing – and is often disrupted in disease conditions. Despite intense research pointing toward a dynamic interplay between glutamate, dopamine (DA), and serotonin (5-HT) neurotransmission, their precise circuit and synaptic mechanisms regulating their role in striatal plasticity are still unclear. Here, we analyze the role of serotonergic raphe-striatal innervation in the regulation of DA-dependent corticostriatal plasticity. MethodsMice (males and females, 2–6 months of age) were housed in standard plexiglass cages at constant temperature (22 ± 1°C) and maintained on a 12/12h light/dark cycle with food and demineralized water ad libitum. In the present study, we used a knock-in mouse line in which the green fluorescent protein reporter gene (GFP) replaced the I Tph2 exon (Tph2GFP mice), allowing selective expression of GFP in the whole 5-HT system, highlighting both somata and neuritis of serotonergic neurons. Heterozygous, Tph2+/GFP, mice were intercrossed to obtain experimental cohorts, which included Wild-type (Tph2+/+), Heterozygous (Tph2+/GFP), and Mutant serotonin-depleted (Tph2GFP/GFP) animals. ResultsUsing male and female mice, carrying on different Tph2 gene dosages, we show that Tph2 gene modulation results in sex-specific corticostriatal abnormalities, encompassing the abnormal amplitude of spontaneous glutamatergic transmission and the loss of Long Term Potentiation (LTP) in Tph2GFP/GFP mice of both sexes, while this form of plasticity is normally expressed in control mice (Tph2+/+). Once LTP is induced, only the Tph2+/GFP female mice present a loss of synaptic depotentiation. ConclusionWe showed a relevant role of the interaction between dopaminergic and serotonergic systems in controlling striatal synaptic plasticity. Overall, our data unveil that 5-HT plays a primary role in regulating DA-dependent corticostriatal plasticity in a sex-related manner and propose altered 5-HT levels as a critical determinant of disease-associated plasticity defects.

Loss of Long-Term Potentiation at Hippocampal Output Synapses in Experimental Temporal Lobe Epilepsy.

Patients suffering from temporal lobe epilepsy (TLE) show severe problems in hippocampus dependent memory consolidation. Memory consolidation strongly depends on an intact dialog between the hippocampus and neocortical structures. Deficits in hippocampal signal transmission are known to provoke disturbances in memory formation. In the present study, we investigate changes of synaptic plasticity at hippocampal output structures in an experimental animal model of TLE. In pilocarpine-treated rats, we found suppressed long-term potentiation (LTP) in hippocampal and parahippocampal regions such as the subiculum and the entorhinal cortex (EC). Subsequently we focused on the subiculum, serving as the major relay station between the hippocampus proper and downstream structures. In control animals, subicular pyramidal cells express different forms of LTP depending on their intrinsic firing pattern. In line with our extracellular recordings, we could show that LTP could only be induced in a minority of subicular pyramidal neurons. We demonstrate that a well-characterized cAMP-dependent signaling pathway involved in presynaptic forms of LTP is perturbed in pilocarpine-treated animals. Our findings suggest that in TLE, disturbances of synaptic plasticity may influence the information flow between the hippocampus and the neocortex.

Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.

Postsynaptic GABABRs Inhibit L-Type Calcium Channels and Abolish Long-Term Potentiation in Hippocampal Somatostatin Interneurons

Inhibition provided by a diverse set of local GABAergic interneurons (INs) activates both ionotropic GABAA and metabotropic GABAB receptors. Despite the fact that GABAB receptors represent a major source of inhibition onto INs, little is known of their function in distinct IN subtypes. Here we show that while the archetypal dendritic-inhibitory somatostatin-expressing INs (SOM-INs ) possess high levels of GABAB receptors and G-protein coupled inward-rectifying K (Kir3) channels on their somato-dendritic surface, they fail to produce significant postsynaptic inhibitory currents. Instead, GABAB receptors selectively inhibit dendritic CaV1.2 (L- type) Ca2 channels on dendrites of SOM-INs, leading to attenuation of calcium influx and loss of long-term potentiation at excitatory input synapses onto these INs. These data provide a novel mechanism by which GABABRs can contribute to disinhibition and control of efficacy of CA3 and entorhinal cortex synaptic inputs in hippocampal networks.

Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

The Relation Between Long-Term Synaptic Plasticity at Glutamatergic Synapses in the Amygdala and Fear Learning in Adult Heterozygous BDNF-Knockout Mice.

Brain-derived neurotrophic factor (BDNF) heterozygous knockout mice (BDNF+/- mice) show fear learning deficits from 3 months of age onwards. Here, we addressed the question how this learning deficit correlates with altered long-term potentiation (LTP) in the cortical synaptic input to the lateral amygdala (LA) and at downstream intra-amygdala synapses in BDNF+/- mice. Our results reveal that the fear learning deficit in BDNF+/- mice was not paralleled by a loss of LTP, neither at cortical inputs to the LA nor at downstream intra-amygdala glutamatergic synapses. As we did observe early fear memory (30 min after training) in BDNF+/- mice while long-term memory (24 h post-training) was absent, the stable LTP in cortico-LA and downstream synapses is in line with the intact acquisition of fear memories. Ex vivo recordings in acute slices of fear-conditioned wildtype (WT) mice revealed that fear learning induces long-lasting changes at cortico-LA synapses that occluded generation of LTP 4 and 24 h after training. Overall, our data show that the intact LTP in the tested amygdala circuits is consistent with intact acquisition of fear memories in both WT and BDNF+/- mice. In addition, the lack of learning-induced long-term changes at cortico-LA synapses in BDNF+/- mice parallels the observed deficit in fear memory consolidation.

Memantine Reduced Cell Death, Astrogliosis, and Functional Deficits in an in vitro Model of Repetitive Mild Traumatic Brain Injury.

Clinical studies suggest that athletes with a history of concussion may be at risk for additional mild traumatic brain injury (mTBI), and repetitive exposure to mTBI acutely increases risk for more significant and persistent symptoms and increases future risk for developing neurodegenerative diseases. Currently, symptoms of mTBI are managed with rest and pain medication; there are no drugs approved by the Food and Drug Administration (FDA) that target the biochemical pathology underlying mTBI to treat or prevent acute and long-term effects of repetitive mTBI. Memantine is an FDA-approved drug for treating Alzheimer's disease, and also was shown to be neuroprotective in rodents following a single, moderate to severe TBI. Therefore, we investigated the potential for memantine to mitigate negative outcomes from repetitive mild stretch injury in organotypical hippocampal slice cultures. Samples received two injuries 24 h apart; injury resulted in significant cell death, loss of long-term potentiation (LTP), and astrogliosis compared with naïve, uninjured samples. Delivery of 1.5 μM memantine 1 h following each stretch significantly reduced the effect of injury for all outcome measures, and did not alter those outcome measures that were unaffected by the injury. Therefore, memantine warrants further pre-clinical and clinical investigation for its therapeutic efficacy to prevent cognitive deficits and neuropathology from multiple mTBIs.

Electrophysiological and Pathological Characterization of the Period of Heightened Vulnerability to Repetitive Injury in an in Vitro Stretch Model.

Clinical studies suggest that repeat exposures to mild traumatic brain injury (mTBI) or concussion, such as sports-related mTBI, result in verbal, memory, and motor deficits that can progressively worsen and take longer for recovery with each additional concussion. Pre-clinical studies suggest that mild mechanical injury of the brain can initiate a period of heightened vulnerability during which the brain is more susceptible to a subsequent mild injury. It is unknown how long this period of heightened vulnerability lasts and, as a result, appropriate return-to-play guidelines for athletes who have sustained sports-related mTBI could be better clarified. To better understand this pathology and define the duration of heightened vulnerability to subsequent exposure, we employed a well-defined stretch injury model to mechanically stimulate organotypic hippocampal slice cultures (OHSCs) and evaluated both electrophysiological and pathological markers of injury. We found that an initial mild stretch initiated a period of heightened vulnerability to a subsequent stretch that lasted at least 24 h. Two mild stretch injuries delivered 24 h apart significantly increased tissue injury, including cell death, damage to dendrites, increased nitrite production, astrogliosis, and loss of long-term potentiation (LTP). Cell loss, dendrite damage, and nitrite production were not significantly increased when the inter-injury interval was increased to 72 h; however, LTP deficits and astrogliosis persisted. An interval of 144 h was sufficient to prevent the detrimental effects of repetitive stretch. Improved understanding of the brain's response to repetitive mTBI in vitro may aid in translational studies, informing rest periods for the injured athlete.

Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice.

The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-d-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry.

Enhanced long term potentiation and decreased AMPA receptor desensitization in the acute period following a single kainate induced early life seizure

Neonatal seizures are associated with long term disabilities including epilepsy and cognitive deficits. Using a neonatal seizure rat model that does not develop epilepsy, but develops a phenotype consistent with other models of intellectual disability (ID) and autism spectrum disorders (ASD), we sought to isolate the acute effects of a single episode of early life seizure on hippocampal CA1 synaptic development and plasticity. We have previously shown chronic changes in glutamatergic synapses, loss of long term potentiation (LTP) and enhanced long term depression (LTD), in the adult male rat ~50days following kainic acid (KA) induced early life seizure (KA-ELS) in post-natal (P) 7day old male Sprague–Dawley rats. In the present work, we examined the electrophysiological properties and expression levels of glutamate receptors in the acute period, 2 and 7days, post KA-ELS. Our results show for the first time enhanced LTP 7days after KA-ELS, but no change 2days post KA-ELS. Additionally, we report that ionotropic α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid type glutamate receptor (AMPAR) desensitization is decreased in the same time frame, with no changes in AMPAR expression, phosphorylation, or membrane insertion. Inappropriate enhancement of the synaptic connections in the acute period after the seizure could alter the normal patterning of synaptic development in the hippocampus during this critical period and contribute to learning deficits. Thus, this study demonstrates a novel mechanism by which KA-ELS alters early network properties that potentially lead to adverse outcomes.

Region- and age-dependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer's disease

To characterize the mechanisms underlying region- and age-dependent hippocampal synaptic dysfunction in Alzheimer's disease, we used transgenic CRND8 mice, expressing the Swedish-Indiana APP mutation. In 2-month-old mice, no β-amyloid plaques deposition, but the presence of soluble oligomers, were found in CA1 area but not in dentate gyrus (DG). At this age, long-term potentiation (LTP) was reduced selectively in CA1. In 6-month-old mice, the presence of soluble oligomers was accompanied by accumulation of β-amyloid plaques and decreased LTP in CA1 and DG regions. In both regions, the loss of LTP was linked to reduced N-methyl-D-aspartate (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) current ratio. The acetylcholine-esterase inhibitor, neostigmine rescued LTP in CA1 area at early stage of the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects were associated with a normalization of the NMDA to AMPA ratio. The association between the recovery of LTP and the normalization of the NMDA to AMPA ratio provides information on new possible therapeutic strategies in Alzheimer's disease.

Abstract TMP70: Reduced Hippocampal Synapses Underlie Loss of Long-Term Potentiation after Experimental Subarachnoid Hemorrhage

Background: Patients who survive aneurysmal subarachnoid hemorrhage (SAH) often have deficits in learning, memory and executive function, although structural brain damage may not be detectable. We previously reported that rodents with SAH develop cognitive deficits and loss of long-term potentiation (LTP), a probable electrophysiological correlate of learning and memory. We hypothesize that loss of LTP may be caused by diminished synapses and/or dysfunction of synaptic molecules responsible for LTP, and that this occurs without neuronal death. Methods: SAH was created by injection of 300 μl of fresh, unheparinized arterial blood into the prechiasmatic cistern of Sprague-Dawley rats (300-350g). Controls were injected with the same amount of saline. Cell death was detected with Fluoro-jade B and TUNEL staining. The number of synapses in dendritic layer of CA1 was quantified by double immunohistochemical staining of MAP2 and synaptophysin, or directly by transmission electron microscopy. Glutamate receptor subunits (GluR1/2) and CaM kinase II were quantified by immunohistochemical staining. Superoxide and nitric oxide (NO) concentrations in freshly homogenized hippocampal tissues were detected by spectrophotometry with DAF-2DA and MCLA dyes. Results: In the dendritic area of CA1, the number of synapses was significantly decreased after SAH compared to controls (54±4/image for SAH, 74±3 for controls, p<0.001). Similarly, the expression of GluR1, GluR2 and CaM kinase II was decreased in SAH rats. Decreased superoxide (0.038±0.006 for SAH, 0.059±0.01 for control p<0.001) but increased NO was detected in rats with SAH as compared to controls (1251±118 for SAH, 518±118 for controls, p<0.001). Fluoro-jade B and TUNEL staining disclosed no to minimal CA1 cell death. Conclusions: Loss of LTP after SAH in rats may be due to a synaptic plasticity rather than cell death. Decreased immunoreactivity to GluR1, GluR2 and CaM kinase II suggests reduction in key proteins that mediator LTP may also contribute. Decreased superoxide and increased NO suggest oxidative stress is involved in the loss of LTP.

DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain

The transmembrane protein deleted in colorectal cancer (DCC) and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP), intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR) function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory.

The Molecular Assembly of Amyloid Aβ Controls Its Neurotoxicity and Binding to Cellular Proteins

Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1–40 and Aβ 1–42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity.

Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats

One of the major complications after subarachnoid hemorrhage (SAH) is angiographic vasospasm in the large arteries at the base of the brain. However, a clinical trial of clazosentan demonstrated a 65% relative risk reduction in angiographic vasospasm but no effect on mortality or clinical outcome, raising questions about the role of angiographic vasospasm played in outcome after SAH. The purpose of this study was to determine if reducing or reversing angiographic vasospasm with clazosentan reduced other secondary complications such as microthromboembolism, loss of long-term potentiation (LTP) and neuronal cell death in a rat model of SAH. SAH in rats was created by injection of 300 μl non-heparinized autologous blood into the pre-chiasmatic cistern. Clazosentan, 10 mg/kg bolus, or vehicle control was administered 1 h after SAH intravenously, followed by a continuous infusion (1 mg/kg/h) into the jugular vein using an osmotic pump. Rats treated with clazosentan had less large-artery vasospsam compared to vehicle-treated controls. However, clazosentan did not prevent the formation of microthromboemboli, neuronal cell death and degeneration and loss of LTP, suggesting there is a dissociation between large-artery angiographic vasospasm and other secondary complications of SAH. This result suggests that alleviation of angiographic vasospasm alone may not be sufficient to prevent other secondary complications or that off-target drug effects after systemic administration of clazosentan counteract the beneficial effects on angiographic vasospasm.

Analyzing the Role of NCKX2 in Hippocampal Long Term Potentiation

Na+/Ca2+ exchangers control clearance of cytosolic Ca2+ following a signaling event when Ca2+ is elevated due to their low-affinity/high capacity transport properties. NCKX2 is a member of the family of K+-dependent Na+/Ca2+-exchangers, and is abundant in brain neurons. Targeted knockout of the NCKX2 gene results in a profound loss of long term potentiation and an increase in long term depression at hippocampal Schaffer/CA1 synapses. We examined the expression of a variety of synaptic molecules when NCKX2 is knocked out to disclose the role of NCKX2 in hippocampal plasticity. Co -localization experiments using confocal and electron microscopy were conducted to define the location of NCKX2 in hippocampus. Immunoblot results from whole brain lysates showed that GluR2/3 and NMDA-receptor 1 were reduced in NCKX2 knockout mice. There was no statistical difference in immunoblot for CamKII, PSD95, or GluR1 between wild type and the knockout. In hippocampus phospho-CamKII was upregulated, and small but insignificant changes were found in the expression of other synaptic marker proteins. Co-localization analyses showed minimal overlap of NCKX2 with either the post synaptic marker CamKII or the presynaptic markers synapsin, synaptophysin or VGLUT-1. Immunocytochemistry revealed a decrease in net MAP-2 label in the CA3 region of knockout animals that correlates to a reduction in the number of neuronal profiles and increase in DAPI-labeled nuclei, suggesting neuronal loss and glial cell proliferation. From the above experiments, we can for first time approach the idea of the exact location of NCKX2. Expression change for various synaptic molecules in hippocampus is not obvious, but rather loss of CA3 neurons and the associated Schaeffer collateral projection to CA1, potentially resulting from changes in calcium dynamics when NCKX2 is knocked out.

The new pyridoindole antioxidant SMe1EC2 and its intervention in hypoxia/hypoglycemia-induced impairment of long-term potentiation in rat hippocampus

Previously, the pyridoindole SMe1EC2 was proved to inhibit lipoperoxidation and carbonylation of proteins in rat brain cortex in the system Fe2+/ascorbate and improvement of resistance of the rat hippocampus was reported against ischemic conditions in vitro (hypoxia/hypoglycemia) expressed by the enhanced neuronal response recovery in reoxygenation. The hippocampus fulfils many of the criteria for a neuronal correlate of learning and memory. Recently, an impairment of hippocampal long-term potentiation (LTP) was reported under oxidative stress. Different therapies, including antioxidants, have been studied intensively concerning the impairment of neuronal plasticity. In this study marked reduction of LTP, elicited by a single burst (100 Hz, 1s) in the CA3-CA1 area of rat hippocampal slices, was shown due to transient hypoxia/hypoglycemia compared to control slices. On the basis of previously reported antioxidant and neuroprotective effects of SMe1EC2, its effect on loss of LTP in the hippocampus due to ischemic conditions was studied in vitro. The pyridoindole tested improved hypoxia/hypoglycemia-induced reduction of LTP compared to untreated hypoxic slices. An opposite effect of SMe1EC2 on LTP induction was found in control slices. The mechanism of SMe1EC2 action on LTP in ischemic conditions has been suggested to differ from the mechanism of its effect in “normoxia” and may be due to different redox status in control and ischemic brain tissue. The manifested LTP-protective effect of SMe1EC2 observed in the rat hippocampus exposed to ischemia in vitro may find exploitation in therapy associated with injured neuronal plasticity in some conditions, including ischemia, trauma and aging in man.

Loss of long-term potentiation in the hippocampus after experimental subarachnoid hemorrhage in rats

Survivors of aneurysmal subarachnoid hemorrhage (SAH) often suffer from cognitive impairment such as memory loss. However, the underlying mechanisms of these impairments are not known. Long-term potentiation (LTP) of synapses in the hippocampus is generally regarded as a molecular substrate of memory. The purpose of this study was to examine the effect of SAH on LTP in the hippocampal Schaffer collateral (CA3–CA1) pathway in a rat model of SAH. We found SAH caused significant vasospasm of the middle cerebral artery (MCA) compared to saline injected or sham controls ( P<0.001). Basic neurotransmission quantified as excitatory post synaptic and spike response from animals with SAH were significantly decreased as compared to naive controls ( P<0.05). However, sham operated and saline injected controls showed similar amplitude as naive controls. This suggests that reduction in basic neurotransmission is due to blood in the subarachnoid space. Similarly, analysis of LTP demonstrated that naive, sham and saline controls have a 92±16%, 69±27% and 71±14% increase over the baseline in the average spike amplitude following high frequency stimulation (HFS), respectively. This indicates the presence of LTP ( P<0.05). In contrast, the spike amplitude in animals of SAH returned to baseline level within 60 min post HFS indicating the absence of LTP. We conclude that SAH caused vasospasm of the MCA that was associated with disrupted basic neurotransmission and plasticity at CA3–CA1 synapses. These changes might be accountable for the memory loss in humans with SAH.

Impaired Plasticity at Specific Subset of Striatal Synapses in the Ts65Dn Mouse Model of Down Syndrome

Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation. There is limited insight into the biological basis for the cognitive and motor deficits in DS. Because the striatum plays a key role in the regulation and learning of voluntary movements and in cognitive processes, our study was aimed at investigating striatal synaptic transmission and plasticity in a well-accepted genetic model of DS. Electrophysiological recordings were performed in a corticostriatal slice preparation from trisomic (Ts65Dn) and wild-type mice. Synaptic properties and plasticity, long-term potentiation (LTP) and long-term depression (LTD), were investigated. The basal electrophysiological properties of striatal principal spiny neurons and cholinergic interneurons were spared in the Ts65Dn mouse model of DS. Striatal principal spiny neurons from Ts65Dn mice maintained their ability to undergo LTP and LTD. Conversely, LTP was lost in striatal cholinergic interneurons of Ts65Dn mice. The loss of LTP in striatal cholinergic interneurons of Ts65Dn mice was accompanied by a severe impairment of endogenous cholinergic signaling within the striatum. The intrastriatal cholinergic system that was thought to be spared in DS is functionally altered in the Ts65Dn genetic model of DS. Altered cholinergic transmission might play a critical role in the pathophysiology of motor and cognitive deficits in DS, leading to an abnormal processing of neuronal inputs within the basal ganglia. Targeting striatal cholinergic transmission might represent a new therapeutic strategy in DS.